A Phase I Study to Assess the Safety, Tolerability and PK of Ceftazidime-Avibactam in Healthy Chinese Subjects

A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of Ceftazidime-Avibactam Administered as Single and Repeated Intravenous Doses in Healthy Chinese Subjects

Investigate the safety and tolerability, as well as PK profile of ceftazidime-avibactam (CAZ -AVI) administered in single and repeated intravenous (IV) infusions in healthy Chinese subjects.This study data will be used to support CAZ-AVI NDA in China.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: 0.9% Normal Saline; Drug: CAZ-AVI

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study-specific procedures.
• Healthy male and female (of non-child bearing potential) Chinese subjects, with suitable veins for cannulation or repeated venipuncture
• BMI 19 to 24 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg.

Key Exclusion Criteria:

• Any clinical condition requiring the regular use of any medication.
• Consumption of alcohol, drug, tobacco (cigarettes).
• Sensitive to any food, or any serious reaction to carbapenem, cephalosporin, or other β-lactam antibiotics.
• Severe medical or psychiatric condition or laboratory abnormality.
• Blood donation.
• 12 lead ECG abnormal.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; IV infusions of 0.9% normal saline	Drug: 0.9% Normal Saline; A single 120 minute IV infusion on Day 1, followed by three times daily (every 8 hours, q8h) as 120 minute IV infusions for 7 days (Day 2 to Day 8), and one single 120 minute IV infusion on Day 9.
Experimental: CAZ-AVI; IV infusion of AVI 500 mg + CAZ 2000 mg.	Drug: CAZ-AVI; A single 120 minute IV infusion on Day 1, followed by three times daily (every 8 hours, q8h) as 120 minute IV infusions for 7 days (Day 2 to Day 8), and one single 120 minute IV infusion on Day 9.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability:Adverse events, vital signs, ECGs, clinical laboratory measurements, physical examinations, oral body temperature	AE: The onset of an AE relative to treatment will be calculated as the time difference between the onset (date and time) of the AE and the start time of the last dose (date and time) prior to the AE; the duration of a resolved AE will be calculated as the difference between the resolution (date and time) of the AE and the onset (date and time) of the AE. Vital signs and oral temperature:Change in BP, pulse rate and oral temperature at each post treatment time point will be calculated as the post treatment measurement value minus the baseline value observed on Day -1. Physical examination: complete physical examination and brief physical examination. ECG: heart rate, RR, PR, QRS, and QT intervals from the 12-lead ECG and the derived variable QTcF. Safety laboratory (hematology, chemistry and urinalysis): Change in laboratory test value at each post treatment time point will be calculated as the post treatment value minus the baseline value observed on Day -1 .	Routine safety assessments, throughout the period that subjects receive CAZ-AVI/PLACEBO up to 5 days following discontinuation of study treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Plasma PK parameters for CAZ and AVI of single dose: Cmax, tmax, Clast, tlast, AUC(0-t), AUC, AUC(0-8), λz, t1/2, Vss, Vz, CL, MRT, etc.	single IV infusion on Day 1
Plasma PK parameters for CAZ and AVI of multi dose: the trough concentration Cmin	Days 6, 7, 8
Plasma PK parameters for CAZ and AVI of repeated infusion: Cmax, tmax, Clast, tlast, AUC(0-t), AUC, AUC(0-8), λz, t1/2, Vss, Vz, CL, MRT, etc.	After repeated infusion On Day 9
Urine PK parameters for CAZ and AVI of single and repeated infusion: Cumulated urinary excretion (amount), percentage of cumulated urinary recovery (% dose) and renal clearance (CLr)	Day 1 and Day 9

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Principal Investigator: Furong Qiu, Shuguang Hospital Affiliated with Shanghai University of TCM

Publications and helpful links

General Publications

• Li J, Lovern M, Green ML, Chiu J, Zhou D, Comisar C, Xiong Y, Hing J, MacPherson M, Wright JG, Riccobene T, Carrothers TJ, Das S. Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups. Clin Transl Sci. 2019 Mar;12(2):151-163. doi: 10.1111/cts.12585. Epub 2018 Sep 28.
• Li J, Learoyd M, Qiu F, Zhu L, Edeki T. A Randomized, Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Ceftazidime-Avibactam in Healthy Chinese Subjects. Clin Drug Investig. 2016 Feb;36(2):119-26. doi: 10.1007/s40261-015-0347-x.

Helpful Links

• D4280C00020_Revised_CSP_1_redacted_protocol

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: July 25, 2013
• First Submitted That Met QC Criteria: August 9, 2013
• First Posted (Estimate): August 12, 2013

Study Record Updates

• Last Update Posted (Actual): September 5, 2017
• Last Update Submitted That Met QC Criteria: September 1, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: CAZ-AVI China phase I PK study
• Other Study ID Numbers: D4280C00020